Professor Lee Smith

Professor Lee Smith

Pro Vice-Chancellor

Office PVC - Science

Career Summary

Biography

Professor Lee Smith began his career with a PhD in Molecular Genetics at the University of Warwick. This was followed by two postdoctoral positions at the MRC Mammalian Genetics Unit in Harwell UK before moving to Edinburgh in 2006 to lead a program of research within the MRC Human Reproductive Sciences Unit.

In 2012, Lee was promoted to Chair of Genetic Endocrinology and Principal Investigator at the MRC Centre for Reproductive Health within the University of Edinburgh. In 2016, Lee was promoted to Head of Male Health Research, MRC Centre for Reproductive Health, overseeing three research teams with a total of 28 researchers.

Lee moved to the University of Newcastle in early 2017 to take up the position of Pro Vice-Chancellor, Faculty of Science.

Research Expertise

With a research focus on ‘testis control of androgen production’, Lee is focussed on exploiting the stem cell niche within the testis to manipulate androgens as a therapeutic tool for human health benefit. Though responsible for a wide portfoilio of research projects in this area, Lee is perhaps best known for his work examining the role of androgen signalling in male reproductive and other tissues, specifically using cell-specific conditional gene targeting of androgen receptor to reveal a hitherto undescribed complex network of paracrine signalling underpinning control of male tissues.

Lee’s contributions have fundamentally changed our understanding of testicular development and function. His ability to attract significant funding for research in this area is strengthened by his publication record and advocacy of the importance of research to funders, the media, the public and new researchers. This is reflected in the fact that, at the time of appointment, Lee was the youngest Full Professor at the University of Edinburgh (aged 37).

In 2016, Lee was honoured by the American Society of Andrology with the 2016 Matthew P. Hardy Young Andrologist Award, awarded to a researcher under the age of 45 who has made an exceptional contribution to andrology research.

Teaching Expertise

Lee has lectured from 2007 at the University of Edinburgh in reproductive biology, experimental systems, sex determination, Paracrine signalling module – testis function and male reproductive health. In addition Lee has supervised 26 post-graduate students.

Administrative Expertise

In additon to several administrative roles at the University of Edinburgh, Lee has served on the UK MRC Populations and Systems Medicine grant awarding board, and as a member of the BBSRC pool of experts. Lee is also a member of the Editorial Boards of Andrology and Molecular and Cellular Endocrinology. He is a journal referee for in excess of 20 journals and regularly reviews grant applications for international funding panels from across the world.

Qualifications

  • Doctor of Philosophy, University of Warwick - England
  • Bachelor of Science (Honours), University of Leicester - UK

Keywords

  • Biotechnology
  • Endocrinology
  • Fertility regulation
  • Genetics
  • Infertility
  • Reproductive Biology
  • Reproductive Sciences

Professional Experience

UON Appointment

Title Organisation / Department
Professor University of Newcastle
School of Environmental and Life Sciences
Australia
Professor University of Newcastle
Office PVC - Science
Australia

Academic appointment

Dates Title Organisation / Department
1/01/2015 - 31/12/2016 Head of Male Health Research University of Edinburgh
Medical Research Council (MRC) Centre for Reproductive Health
United Kingdom

Professional appointment

Dates Title Organisation / Department
1/01/2012 - 31/12/2016 Personal Chair of Genetic Endocrinology - Principal Investigator University of Edinburgh
Medical Research Council (MRC) Centre for Reproductive Health
United Kingdom

Invitations

Keynote Speaker

Year Title / Rationale
2015 Androgens in lifelong health and wellbeing
American Testis Workshop

Speaker

Year Title / Rationale
2016 Androgenic control of male health
2016 Viral gene therapy as a single-dose sterilant?
2016 Leydig cells: controllers of lifelong male health?
2016 How does testosterone influence male health; is it all just sex and violence?
2016 Its time for ‘T’! Testosterone and lifelong male health
Public  Lecture  series
2015 Mouse models and male fertility research
2015 Androgenic control of male health
2014 Paracrine control of testicualr androgen signalling
2014 The control of androgen signalling – implications for lifelong male health
2014 The role of Sertoli cells in the prepubertal testis
18th European Testis Workshop
2014 Development of a single dose sterilant targeting Androgen Receptor
2014 The role of Sertoli cells in the prepubertal testis
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Chapter (4 outputs)

Year Citation Altmetrics Link
2017 O'Hara L, Smith LB, 'Mouse Genetics: how does it inform male fertility research?', The Sperm Cell Production, Maturation, Fertilization, Regeneration, Cambridge University Press, Cambridge, UK (2017)
2016 Smith LB, O¿Hara L, 'Development and Characterisation of Cell-Specific Androgen Receptor Knockout Mice', The Nuclear Receptor Superfamily: Methods and Protocols, Springer, New York 219-248 (2016)
2016 Smith LB, O¿Hara L, 'Development and Characterisation of Cell-Specific Androgen Receptor Knockout Mice', The Nuclear Receptor Superfamily: Methods and Protocols, Springer, New York 219-248 (2016)
2014 Smith LB, Walker WH, 'Hormone Signaling in the Testis', Knobil and Neill's Physiology of Reproduction: Two-Volume Set 637-690 (2014)

© 2015 Elsevier Inc. All rights reserved. A complex milieu of hormones initiates diverse signaling pathways within and between cells of the testis to support the processes of ste... [more]

© 2015 Elsevier Inc. All rights reserved. A complex milieu of hormones initiates diverse signaling pathways within and between cells of the testis to support the processes of steroidogenesis, spermatogenesis, and ultimately male fertility. In this chapter, we discus s the roles, mechanisms, and impacts of hormone signaling within the testis. We describe the mechanisms by which luteinizing hormone promotes the production of testosterone, a hormone essential for spermatogenesis. We use information obtained from cell-specific knockout studies of the androgen receptor as well as cellular and gene expression studies to describe the multifaceted actions of testosterone within the testis. We examine the multiple signaling pathways regulated by follicle-stimulating hormone in Sertoli cells and discuss how these pathways interface with testosterone signaling. In addition, we review how thyroid hormone regulates the proliferation of Sertoli cells and thus determines the capacity for sperm production. Furthermore, the paracrine functions of testis-derived hormones, including estrogen as well as activin and inhibin, are discussed. Finally, the contributions of other hormones that act to fine-tune testicular functions in response to environmental inputs are discussed. Together, these combined data paint a vivid picture of a complex, hormone-regulated signaling environment in the testis that acts to ensure that correct testicular function is maintained throughout life.

DOI 10.1016/B978-0-12-397175-3.00016-8
Citations Scopus - 4
Show 1 more chapter

Journal article (70 outputs)

Year Citation Altmetrics Link
2017 O'Hara L, Smith LB, 'The Genetics of Androgen Receptor Signalling in Male Fertility', Monographs in Human Genetics, 21 86-100 (2017)

© 2017 S. Karger AG, Basel. The androgen testosterone has an essential trophic role in the development of male physiology and in adult spermatogenesis and fertility. Testosterone... [more]

© 2017 S. Karger AG, Basel. The androgen testosterone has an essential trophic role in the development of male physiology and in adult spermatogenesis and fertility. Testosterone mainly exerts its effect through the androgen receptor (AR), a ligand-Activated transcription factor that is activated by binding the androgens testosterone or dihydrotestosterone. Mutations in AR can result in the genetic disorder androgen insensitivity syndrome, which results in a feminised phenotype and developmental problems, including cryptorchidism and disrupted spermatogenesis, thus complicating the investigation of the role of AR in adulthood. Transgenic mouse models of conditional AR inactivation have helped to define cell-specific roles for AR in the testis and the wider male reproductive system, and revealed a complex paracrine signalling network that controls fertility through several cell types and differing mechanisms.

DOI 10.1159/000477280
2017 Hutka M, Smith LB, Mitchell RT, 'Xenotransplantation as a model for human testicular development', Differentiation, 97 44-53 (2017) [C1]

© 2017 International Society of Differentiation The developing male reproductive system may be sensitive to disruption by a wide range of exogenous ¿endocrine disruptors¿. In-u... [more]

© 2017 International Society of Differentiation The developing male reproductive system may be sensitive to disruption by a wide range of exogenous ¿endocrine disruptors¿. In-utero exposure to environmental chemicals and pharmaceuticals have been hypothesized to have an impact in the increasing incidence of male reproductive disorders. The vulnerability to adverse effects as a consequence of such exposures is elevated during a specific ¿window of susceptibility¿ in fetal life referred to as the masculinisation programing window (MPW). Exposures that occur during prepuberty, such as chemotherapy treatment for cancer during childhood, may also affect future fertility. Much of our current knowledge about fetal and early postnatal human testicular development derives from studies conducted in animal models predictive for humans. Therefore, over recent years, testicular transplantation has been employed as a ¿direct¿ approach to understand the development of human fetal and prepubertal testis in health and disease. In this review we describe the potential use of human testis xenotransplantation to study testicular development and its application for (i) assessing the effects of environmental exposures in humans, and (ii) establishing fertility preservation options for prepubertal boys with cancer.

DOI 10.1016/j.diff.2017.09.001
2017 Rebourcet D, Darbey A, Monteiro A, Soffientini U, Tsai YT, Handel I, et al., 'Sertoli Cell Number Defines and Predicts Germ and Leydig Cell Population Sizes in the Adult Mouse Testis', ENDOCRINOLOGY, 158 2955-2969 (2017) [C1]
DOI 10.1210/en.2017-00196
2017 Ribeiro MCW, 'Novel androgen-induced activity of an antimicrobial ß-defensin: Regulation of Wolffian duct morphogenesis', Molecular and Cellular Endocrinology, 442 142-152 (2017)
DOI 10.1016/j.mce.2016.12.016
2017 Patel SH, O'Hara L, Atanassova N, Smith SE, Curley MK, Rebourcet D, et al., 'Low-dose tamoxifen treatment in juvenile males has long-term adverse effects on the reproductive system: implications for inducible transgenics.', Scientific Reports, 7 (2017) [C1]
DOI 10.1038/s41598-017-09016-4
2017 Banks G, Lassi G, Hoerder-Suabedissen A, Tinarelli F, Simon MM, Wilcox A, et al., 'A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.', Mol Psychiatry, (2017)
DOI 10.1038/mp.2017.54
2017 Takov K, Wu J, Denvir MA, Smith LB, Hadoke PWF, 'The role of androgen receptors in atherosclerosis.', Molecular and cellular endocrinology, (2017)
DOI 10.1016/j.mce.2017.10.006
2017 Engels M, Span PN, Mitchell RT, Heuvel JJTM, Marijnissen-van Zanten MA, van Herwaarden AE, et al., 'GATA transcription factors in testicular adrenal rest tumours.', Endocrine connections, (2017)
DOI 10.1530/ec-17-0215
2016 O Hara L, Livigni A, Theo T, Boyer B, Angus T, Wright D, et al., 'Modelling the Structure and Dynamics of Biological Pathways', PLoS Biology, 14 (2016) [C1]
DOI 10.1371/journal.pbio.1002530
Citations Scopus - 2Web of Science - 2
2016 Cobice R, Livingstone DEW, Mackay CL, Goodwin RJA, Smith L, Walker BR, Andrew R, 'Spatial Localization and Quantitation of Androgens in Mouse Testis by Mass Spectrometry Imaging', Analytical Chemistry, 88 10362-10367 (2016) [C1]
DOI 10.1021/acs.analchem.6b02242
Citations Scopus - 1Web of Science - 2
2016 Smith LB, 'Nonclassical testosterone signaling: A new pathway controlling spermatogenesis?', Biology of Reproduction, 94 1-2 (2016) [C1]
DOI 10.1095/biolreprod.115.137950
Citations Scopus - 3Web of Science - 3
2016 Rebourcet LB, Wu J, Cruickshanks L, Smith SE, Milne L, Fernando A, et al., 'Sertoli cells modulate testicular vascular network development, structure, and function to influence circulating testosterone concentrations in adult male mice', Endocrinology, 157 2479-2488 (2016) [C1]
DOI 10.1210/en.2016-1156
Citations Scopus - 1Web of Science - 2
2016 Wu J, Hadoke PWF, Takov K, Korczak A, Denvir MA, Smith LB, 'Influence of androgen receptor in vascular cells on reperfusion following hindlimb ischaemia', PLoS ONE, 11 (2016) [C1]
DOI 10.1371/journal.pone.0154987
2016 Stanton RI, Foo CFH, Rainczuk A, Stephens AN, Condina M, O' Donnell L, et al., 'Mapping the testicular interstitial fluid proteome from normal rats', Proteomics, 16 2391-2402 (2016) [C1]
DOI 10.1002/pmic.201600107
Citations Scopus - 1Web of Science - 1
2016 Zhu VE, Hadoke PWF, Wu J, Vesey AT, Lerman DA, Dweck MR, et al., 'Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification', Scientific Reports, 6 (2016) [C1]
DOI 10.1038/srep24807
Citations Scopus - 10Web of Science - 11
2015 Mitchell RT, Mungall W, McKinnell C, Sharpe RM, Cruickshanks L, Milne L, Smith LB, 'Anogenital Distance Plasticity in Adulthood: Implications for Its Use as a Biomarker of Fetal Androgen Action', ENDOCRINOLOGY, 156 24-31 (2015) [C1]
DOI 10.1210/en.2014-1534
Citations Scopus - 18Web of Science - 19
2015 O'Hara L, McInnes K, Simitsidellis I, Morgan S, Atanassova N, Slowikowska-Hilczer J, et al., 'Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men', FASEB JOURNAL, 29 894-910 (2015) [C1]
DOI 10.1096/fj.14-255729
Citations Scopus - 13Web of Science - 11
2015 Willems A, Roesl C, Mitchell RT, Milne L, Jeffery N, Smith S, et al., 'Sertoli Cell Androgen Receptor Signalling in Adulthood Is Essential for Post-Meiotic Germ Cell Development', MOLECULAR REPRODUCTION AND DEVELOPMENT, 82 626-627 (2015) [C1]
DOI 10.1002/mrd.22506
Citations Scopus - 2Web of Science - 1
2015 Fijak M, Damm L-J, Wenzel J-P, Aslani F, Walecki M, Wahle E, et al., 'Influence of Testosterone on Inflammatory Response in Testicular Cells and Expression of Transcription Factor Foxp3 in T Cells', AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 74 12-25 (2015) [C1]
DOI 10.1111/aji.12363
Citations Scopus - 7Web of Science - 6
2015 O'Hara L, Smith LB, 'Androgen receptor roles in spermatogenesis and infertility', BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM, 29 595-605 (2015) [C1]
DOI 10.1016/j.beem.2015.04.006
Citations Scopus - 22Web of Science - 14
2015 Chambers T, Smith LB, 'Hormone Imbalances in Men', Topics in Advanced Practice Nursing, 85 74-76 (2015)
2015 Guillermet-Guibert J, Smith LB, Halet G, Whitehead MA, Pearce W, Rebourcet D, et al., 'Novel Role for p110 beta PI 3-Kinase in Male Fertility through Regulation of Androgen Receptor Activity in Sertoli Cells', PLOS GENETICS, 11 (2015) [C1]
DOI 10.1371/journal.pgen.1005304
Citations Scopus - 6Web of Science - 5
2015 O'Hara L, Curley M, Ferreira MT, Cruickshanks L, Milne L, Smith LB, 'y Pituitary Androgen Receptor Signalling Regulates Prolactin but Not Gonadotrophins in the Male Mouse', PLOS ONE, 10 (2015) [C1]
DOI 10.1371/journal.pone.0121657
Citations Scopus - 10Web of Science - 8
2015 van den Driesche S, Macdonald J, Anderson RA, Johnston ZC, Chetty T, Smith LB, et al., 'Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model', SCIENCE TRANSLATIONAL MEDICINE, 7 (2015) [C1]
DOI 10.1126/scitranslmed.aaa4097
Citations Scopus - 17Web of Science - 17
2015 Smith LB, O'Shaughnessy PJ, Rebourcet D, 'Cell-specific ablation in the testis: what have we learned?', ANDROLOGY, 3 1035-1049 (2015) [C1]
DOI 10.1111/andr.12107
Citations Scopus - 5Web of Science - 6
2014 Mitchell RT, E Camacho-Moll M, Macdonald J, Anderson RA, Kelnar CJH, E Camacho-Moll M, et al., 'Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential', Modern Pathology, (2014) [C1]

Testicular germ cell cancer develops from premalignant intratubular germ cell neoplasia, unclassified cells that are believed to arise from failure of normal maturation of fetal g... [more]

Testicular germ cell cancer develops from premalignant intratubular germ cell neoplasia, unclassified cells that are believed to arise from failure of normal maturation of fetal germ cells from gonocytes (OCT4 + /MAGEA4 - ) into pre-spermatogonia (OCT4 - /MAGEA4 + ). Intratubular germ cell neoplasia cell subpopulations based on stage of germ cell differentiation have been described, however the importance of these subpopulations in terms of invasive potential has not been reported. We hypothesized that cells expressing an immature (OCT4 + /MAGEA4 - ) germ cell profile would exhibit an increased proliferation rate compared with those with a mature profile (OCT4 + /MAGEA4 + ). Therefore, we performed triple immunofluorescence and stereology to quantify the different intratubular germ cell neoplasia cell subpopulations, based on expression of germ cell (OCT4, PLAP, AP2¿, MAGEA4, VASA) and proliferation (Ki67) markers, in testis sections from patients with preinvasive disease, seminoma, and non-seminoma. We compared these subpopulations with normal human fetal testis and with seminoma cells. Heterogeneity of protein expression was demonstrated in intratubular germ cell neoplasia cells with respect to gonocyte and spermatogonial markers. It included an embryonic/fetal germ cell subpopulation lacking expression of the definitive intratubular germ cell neoplasia marker OCT4, that did not correspond to a physiological (fetal) germ cell subpopulation. OCT4 + /MAGEA4 - cells showed a significantly increased rate of proliferation compared with the OCT4 + /MAGEA4 + population (12.8 versus 3.4%, P < 0.0001) irrespective of histological tumor type, reflected in the predominance of OCT4 + /MAGEA4 - cells in the invasive tumor component. Surprisingly, OCT4 + /MAGEA4 - cells in patients with preinvasive disease showed significantly higher proliferation compared to those with seminoma or non-seminoma (18.1 versus 10.2 versus 7.2%, P < 0.05, respectively). In conclusion, this study has demonstrated that OCT4 + /MAGEA4 - cells are the most frequent and most proliferative cell population in tubules containing intratubular germ cell neoplasia, which appears to be an important factor in determining invasive potential of intratubular germ cell neoplasia to seminomas.Modern Pathology advance online publication, 24 January 2014; doi:10.1038/modpathol.2013.246.

DOI 10.1038/modpathol.2013.246
Citations Scopus - 12Web of Science - 9
2014 Wu J, Hadoke PWF, Mair I, Lim WG, Miller E, Denvir MA, Smith LB, 'Modulation of neointimal lesion formation by endogenous androgens is independent of vascular androgen receptor', CARDIOVASCULAR RESEARCH, 103 281-290 (2014) [C1]
DOI 10.1093/cvr/cvu142
Citations Scopus - 4Web of Science - 4
2014 Kilcoyne KR, Smith LB, Atanassova N, Macpherson S, McKinnell C, van den Driesche S, et al., 'Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111 E1924-E1932 (2014) [C1]
DOI 10.1073/pnas.1320735111
Citations Scopus - 45Web of Science - 43
2014 Sauter KA, Pridans C, Sehgal A, Tsai YT, Bradford BM, Raza S, et al., 'Pleiotropic effects of extended blockade of CSF1R signaling in adult mice', JOURNAL OF LEUKOCYTE BIOLOGY, 96 265-274 (2014) [C1]
DOI 10.1189/jlb.2A0114-006R
Citations Scopus - 17Web of Science - 11
2014 Rebourcet D, O'Shaughnessy PJ, Pitetti J-L, Monteiro A, O'Hara L, Milne L, et al., 'Sertoli cells control peritubular myoid cell fate and support adult Leydig cell development in the prepubertal testis', DEVELOPMENT, 141 2139-2149 (2014) [C1]
DOI 10.1242/dev.107029
Citations Scopus - 23Web of Science - 21
2014 Smith LB, Walker WH, 'The regulation of spermatogenesis by androgens', SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 30 2-13 (2014) [C1]
DOI 10.1016/j.semcdb.2014.02.012
Citations Scopus - 90Web of Science - 87
2014 Gow DJ, Sauter KA, Pridans C, Moffat L, Sehgal A, Stutchfield BM, et al., 'Characterisation of a Novel Fc Conjugate of Macrophage Colony-stimulating Factor', MOLECULAR THERAPY, 22 1580-1592 (2014) [C1]
DOI 10.1038/mt.2014.112
Citations Scopus - 17Web of Science - 17
2014 O'Hara L, York JP, Zhang P, Smith LB, 'Targeting of GFP-Cre to the Mouse Cyp11a1 Locus Both Drives Cre Recombinase Expression in Steroidogenic Cells and Permits Generation of Cyp11a1 Knock Out Mice', PLOS ONE, 9 (2014) [C1]
DOI 10.1371/journal.pone.0084541
Citations Scopus - 7Web of Science - 8
2014 Rebourcet D, O'Shaughnessy PJ, Monteiro A, Milne L, Cruickshanks L, Jeffrey N, et al., 'Sertoli Cells Maintain Leydig Cell Number and Peritubular Myoid Cell Activity in the Adult Mouse Testis', PLOS ONE, 9 (2014) [C1]
DOI 10.1371/journal.pone.0105687
Citations Scopus - 18Web of Science - 16
2014 Zimmermann C, Romero Y, Warnefors M, Bilican A, Borel C, Smith LB, et al., 'Germ Cell-Specific Targeting of DICER or DGCR8 Reveals a Novel Role for Endo-siRNAs in the Progression of Mammalian Spermatogenesis and Male Fertility', PLOS ONE, 9 (2014) [C1]
DOI 10.1371/journal.pone.0107023
Citations Scopus - 31Web of Science - 24
2013 Hall EA, Keighren M, Ford MJ, Davey T, Jarman AP, Smith LB, et al., 'Acute Versus Chronic Loss of Mammalian Azi1/Cep131 Results in Distinct Ciliary Phenotypes', PLOS GENETICS, 9 (2013) [C1]
DOI 10.1371/journal.pgen.1003928
Citations Scopus - 22Web of Science - 23
2013 Mitchell RT, Sharpe RM, Anderson RA, McKinnell C, Macpherson S, Smith LB, et al., 'Diethylstilboestrol Exposure Does Not Reduce Testosterone Production in Human Fetal Testis Xenografts', PLOS ONE, 8 (2013) [C1]
DOI 10.1371/journal.pone.0061726
Citations Scopus - 21Web of Science - 18
2012 McInnes KJ, Smith LB, Hunger NI, Saunders PTK, Andrew R, Walker BR, 'Deletion of the Androgen Receptor in Adipose Tissue in Male Mice Elevates Retinol Binding Protein 4 and Reveals Independent Effects on Visceral Fat Mass and on Glucose Homeostasis', DIABETES, 61 1072-1081 (2012) [C1]
DOI 10.2337/db11-1136
Citations Scopus - 35Web of Science - 38
2012 Welsh M, Moffat L, Belling K, de Franca LR, Segatelli TM, Saunders PTK, et al., 'Androgen receptor signalling in peritubular myoid cells is essential for normal differentiation and function of adult Leydig cells', INTERNATIONAL JOURNAL OF ANDROLOGY, 35 25-40 (2012)
DOI 10.1111/j.1365-2605.2011.01150.x
Citations Scopus - 26Web of Science - 24
2012 Dean A, Smith LB, Macpherson S, Sharpe RM, 'The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats', INTERNATIONAL JOURNAL OF ANDROLOGY, 35 330-339 (2012) [C1]
DOI 10.1111/j.1365-2605.2011.01236.x
Citations Scopus - 26Web of Science - 28
2012 Smith LB, Milne L, Nelson N, Eddie S, Brown P, Atanassova N, et al., 'KATNAL1 Regulation of Sertoli Cell Microtubule Dynamics Is Essential for Spermiogenesis and Male Fertility', PLOS GENETICS, 8 (2012) [C1]
DOI 10.1371/journal.pgen.1002697
Citations Scopus - 22Web of Science - 22
2012 O'Donnell L, Rhodes D, Smith SJ, Merriner DJ, Clark BJ, Borg C, et al., 'An Essential Role for Katanin p80 and Microtubule Severing in Male Gamete Production', PLOS GENETICS, 8 (2012) [C1]
DOI 10.1371/journal.pgen.1002698
Citations Scopus - 33Web of Science - 28
2012 van den Driesche S, Walker M, McKinnell C, Scott HM, Eddie SL, Mitchell RT, et al., 'Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents', PLOS ONE, 7 (2012) [C1]
DOI 10.1371/journal.pone.0037064
Citations Scopus - 34Web of Science - 30
2012 O'Hara L, Smith LB, 'Androgen receptor signalling in Vascular Endothelial cells is dispensable for spermatogenesis and male fertility', BMC Research Notes, 5 (2012) [C1]

Background: Androgen signalling is essential both for male development and function of the male reproductive system in adulthood. Within the adult testis, Germ cells (GC) do not e... [more]

Background: Androgen signalling is essential both for male development and function of the male reproductive system in adulthood. Within the adult testis, Germ cells (GC) do not express androgen receptor (AR) suggesting androgen-mediated promotion of spermatogenesis must act via AR-expressing somatic cell-types. Several recent studies have exploited the Cre/lox system of conditional gene-targeting to ablate AR function from key somatic cell-types in order to establish the cell-specific role of AR in promotion of male fertility. In this study, we have used a similar approach to specifically ablate AR-signalling from Vascular Endothelial (VE) cells, with a view to defining the significance of androgen signalling within this cell-type on spermatogenesis. Findings. AR expression in VE cells of the testicular vasculature was confirmed using an antibody against AR. A Cre-inducible fluorescent reporter line was used to empirically establish the utility of a mouse line expressing Cre Recombinase driven by the Tie2-Promoter, for targeting VE cells. Immunofluorescent detection revealed expression of YFP (and therefore Cre Recombinase function) limited to VE cells and an interstitial population of cells, believed to be macrophages, that did not express AR. Mating of Tie2-Cre males to females carrying a floxed AR gene produced Vascular Endothelial Androgen Receptor Knockout (VEARKO) mice and littermate controls. Ablation of AR from all VE cells was confirmed; however, no significant differences in bodyweight or reproductive tissue weights could be detected in VEARKO animals and spermatogenesis and fertility was unaffected. Conclusions: We demonstrate the successful generation and empirical validation of a cell-specific knockout of AR from VE cells, and conclude that AR expression in VE cells is not essential for spermatogenesis or male fertility. © 2012 O'Hara et al.

DOI 10.1186/1756-0500-5-16
Citations Scopus - 12
2011 Smith LB, Hadoke PWF, Dyer E, Denvir MA, Brownstein D, Miller E, et al., 'Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome', CARDIOVASCULAR RESEARCH, 90 182-190 (2011) [C1]
DOI 10.1093/cvr/cvq356
Citations Scopus - 22Web of Science - 19
2011 O'Hara L, Welsh M, Saunders PTK, Smith LB, 'Androgen Receptor Expression in the Caput Epididymal Epithelium Is Essential for Development of the Initial Segment and Epididymal Spermatozoa Transit', ENDOCRINOLOGY, 152 718-729 (2011) [C1]
DOI 10.1210/en.2010-0928
Citations Scopus - 42Web of Science - 35
2011 Welsh M, Moffat L, McNeilly A, Brownstein D, Saunders PTK, Sharpe RM, Smith LB, 'Smooth Muscle Cell-Specific Knockout of Androgen Receptor: A New Model for Prostatic Disease', ENDOCRINOLOGY, 152 3541-3551 (2011) [C1]
DOI 10.1210/en.2011-0282
Citations Scopus - 19Web of Science - 19
2011 Smith LB, Saunders PTK, 'The Skeleton: The New Controller of Male Fertility?', CELL, 144 642-+ (2011)
DOI 10.1016/j.cell.2011.02.028
Citations Scopus - 7Web of Science - 5
2011 Orr B, Vanpoucke G, Grace OC, Smith L, Anderson RA, Riddick ACP, et al., 'Expression of pleiotrophin in the prostate is androgen regulated and it functions as an autocrine regulator of mesenchyme and cancer associated fibroblasts and as a paracrine regulator of epithelia', Prostate, 71 305-317 (2011) [C1]

BACKGROUND Androgens and paracrine signaling from mesenchyme/stroma regulate development and disease of the prostate, and gene profiling studies of inductive prostate mesenchyme h... [more]

BACKGROUND Androgens and paracrine signaling from mesenchyme/stroma regulate development and disease of the prostate, and gene profiling studies of inductive prostate mesenchyme have identified candidate molecules such as pleiotrophin (Ptn). METHODS Ptn transcripts and protein were localized by in situ and immunohistochemistry and Ptn mRNA was quantitated by Northern blot and qRT-PCR. Ptn function was examined by addition of hPTN protein to rat ventral prostate organ cultures, primary human fetal prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. RESULTS During development, Ptn transcripts and protein were expressed in ventral mesenchymal pad (VMP) and prostatic mesenchyme. Ptn was localized to mesenchyme surrounding ductal epithelial tips undergoing branching morphogenesis, and was located on the surface of epithelia. hPTN protein stimulated branching morphogenesis and stromal and epithelial proliferation, when added to rat VP cultures, and also stimulated growth of fetal human prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. PTN mRNA was enriched in patient-matched normal prostate fibroblasts versus prostate cancer associated fibroblasts. PTN also showed male enriched expression in fetal human male urethra versus female, and between wt male and ARKO male mice. Transcripts for PTN were upregulated by testosterone in fetal human prostate fibroblasts and organ cultures of female rat VMP. Ptn protein was increased by testosterone in organ cultures of female rat VMP and in rat male urethra compared to female. CONCLUSIONS Our data suggest that in the prostate Ptn functions as a regulator of both mesenchymal and epithelial proliferation, and that androgens regulate Ptn levels. © 2010 Wiley-Liss, Inc.

DOI 10.1002/pros.21244
Citations Scopus - 16
2011 Smith L, 'Good planning and serendipity: Exploiting the Cre/Lox system in the testis', Reproduction, 141 151-161 (2011) [C1]

Over the past 20 years, genetic manipulation has revolutionised our understanding of male reproductive development and function. The advent of transgenic mouse lines has permitted... [more]

Over the past 20 years, genetic manipulation has revolutionised our understanding of male reproductive development and function. The advent of transgenic mouse lines has permitted elegant dissection of previously intractable issues. The development of the Cre/Lox system, which has permitted spatial and temporal localisation of genetic manipulation, has expanded upon this, and now makes up one of the primary approaches underpinning our increasing understanding of testis development and function. The success of conditional gene targeting is largely reliant upon the choice of Cre recombinase expressing mouse line, which is required to specifically target the correct cell type at the correct time. Presupposition that Cre lines will behave as expected has been one of the main oversights in the design of Cre/Lox experiments, as in practice, many Cre lines are prone to ectopic expression (both temporal and spatial), transgene silencing or genetic background effects. Empirical validation of the spatiotemporal profile of Cre expression prior to undertaking conditional gene targeting studies is essential and can be achieved through a combination of molecular and immunohistochemical approaches, along with in vivo examination of reporter gene expression in targeted tissues. This paper details the key considerations associated with exploitation of the Cre/Lox system and highlights a variety of validated Cre lines that have utility for conditional gene targeting within the testis. © 2011 Society for Reproduction and Fertility.

DOI 10.1530/REP-10-0404
Citations Scopus - 27
2011 Denison FC, Smith LB, Muckett PJ, O'Hara L, Carling D, Woods A, 'LKB1 Is an Essential Regulator of Spermatozoa Release during Spermiation in the Mammalian Testis', PLOS ONE, 6 (2011) [C1]
DOI 10.1371/journal.pone.0028306
Citations Scopus - 16Web of Science - 14
2010 Welsh M, Moffat L, Jack L, McNeilly A, Brownstein D, Saunders PTK, et al., 'Deletion of Androgen Receptor in the Smooth Muscle of the Seminal Vesicles Impairs Secretory Function and Alters Its Responsiveness to Exogenous Testosterone and Estradiol', ENDOCRINOLOGY, 151 3374-3385 (2010)
DOI 10.1210/en.2009-1339
Citations Scopus - 19Web of Science - 18
2010 Welsh M, MacLeod DJ, Walker M, Smith LB, Sharpe RM, 'Critical androgen-sensitive periods of rat penis and clitoris development', INTERNATIONAL JOURNAL OF ANDROLOGY, 33 E144-E152 (2010)
DOI 10.1111/j.1365-2605.2009.00978.x
Citations Scopus - 54Web of Science - 42
2010 Willems A, De Gendt K, Allemeersch J, Smith LB, Welsh M, Swinnen JV, Verhoeven G, 'Early effects of Sertoli cell-selective androgen receptor ablation on testicular gene expression', INTERNATIONAL JOURNAL OF ANDROLOGY, 33 507-517 (2010)
DOI 10.1111/j.1365-2605.2009.00964.x
Citations Scopus - 34Web of Science - 29
2010 Welsh M, Sharpe RM, Moffat L, Atanassova N, Saunders PTK, Kilter S, et al., 'Androgen Action via Testicular Arteriole Smooth Muscle Cells Is Important for Leydig Cell Function, Vasomotion and Testicular Fluid Dynamics', PLOS ONE, 5 (2010)
DOI 10.1371/journal.pone.0013632
Citations Scopus - 28Web of Science - 22
2009 Welsh M, Sharpe RM, Walker M, Smith LB, Saunders PTK, 'New Insights into the Role of Androgens in Wolffian Duct Stabilization in Male and Female Rodents', ENDOCRINOLOGY, 150 2472-2480 (2009)
DOI 10.1210/en.2008-0529
Citations Scopus - 26Web of Science - 23
2009 Welsh M, Saunders PTK, Atanassova N, Sharpe RM, Smith LB, 'Androgen action via testicular peritubular myoid cells is essential for male fertility', FASEB JOURNAL, 23 4218-4230 (2009)
DOI 10.1096/fj.09-138347
Citations Scopus - 107Web of Science - 100
2009 Pastorelli LM, Wells S, Fray M, Smith A, Hough T, Harfe BD, et al., 'Genetic analyses reveal a requirement for Dicer1 in the mouse urogenital tract', Mammalian Genome, 20 140-151 (2009)

Despite the increasing interest in other classes of small RNAs, microRNAs (miRNAs) remain the most widely investigated and have been shown to play a role in a number of different ... [more]

Despite the increasing interest in other classes of small RNAs, microRNAs (miRNAs) remain the most widely investigated and have been shown to play a role in a number of different processes in mammals. Many studies investigating miRNA function focus on the processing enzyme Dicer1, which is an RNAseIII protein essential for the biogenesis of active miRNAs through its cleavage of precursor RNA molecules. General deletion of Dicer1 in the mouse confirms that miRNAs are essential for development because embryos lacking Dicer1 fail to reach the end of gastrulation. Here we investigate the role of Dicer1 in urogenital tract development. We utilised a conditional allele of the Dicer1 gene and two Cre-expressing lines, driven by HoxB7 and Amhr2, to investigate the effect of Dicer1 deletion on both male and female reproductive tract development. Data presented here highlight an essential role for Dicer1 in the correct morphogenesis and function of the female reproductive tract and confirm recent findings that suggest Dicer1 is required for female fertility. In addition, HoxB7:Cre-mediated deletion in ureteric bud derivatives leads to a spectrum of anomalies in both males and females, including hydronephrotic kidneys and kidney parenchymal cysts. Male reproductive tract development, however, remains largely unaffected in the absence of Dicer1. Thus, Dicer1 is required for development of the female reproductive tract and also normal kidney morphogenesis. © 2009 Springer Science+Business Media, LLC.

DOI 10.1007/s00335-008-9169-y
Citations Scopus - 59
2008 Welsh M, Saunders PTK, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM, 'Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism', JOURNAL OF CLINICAL INVESTIGATION, 118 1479-1490 (2008)
DOI 10.1172/JCI34241
Citations Scopus - 321Web of Science - 304
2008 Smith L, Willan J, Warr N, Brook FA, Cheeseman M, Sharpe R, et al., 'The maestro (Mro) gene is dispensable for normal sexual development and fertility in mice', PLoS ONE, 3 (2008)

The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microa... [more]

The mammalian gonad arises as a bipotential primordium from which a testis or ovary develops depending on the chromosomal sex of the individual. We have previously used DNA microarrays to screen for novel genes controlling the developmental fate of the indifferent embryonic mouse gonad. Maestro (Mro), which encodes a HEAT-repeat protein, was originally identified as a gene exhibiting sexually dimorphic expression during mouse gonad development. Wholemount in situ hybridisation analysis revealed Mro to be expressed in the embryonic male gonad from approximately 11.5 days post coitum, prior to overt sexual differentiation. No significant expression was detected in female gonads at the same developmental stage. In order to address its physiological function, we have generated mice lacking Maestro using gene targeting. Male and female mice homozygous for a Mro null allele are viable and fertile. We examined gonad development in homozygous male embryos in detail and observed no differences when compared to wild-type controls. Immunohistochemical analysis of homozygous mutant testes of adult mice revealed no overt abnormalities. Expression profiling using DNA microarrays also indicated no significant differences between homozygote embryonic male gonads and controls. We conclude that Maestro is dispensable for normal male sexual development and fertility in laboratory mice; however, the Mro locus itself does have utility as a site for insertion of transgenes for future studies in the fields of sexual development and Sertoli cell function. © 2008 Smith et al.

DOI 10.1371/journal.pone.0004091
Citations Scopus - 4
2007 Frankenberg S, Smith L, Greenfield A, Zernicka-Goetz M, 'Novel gene expression patterns along the proximo-distal axis of the mouse embryo before gastrulation', BMC Developmental Biology, 7 (2007)

Background. To date, the earliest stage at which the orientation of the anterior-posterior axis in the mouse embryo is distinguishable by asymmetric gene expression is shortly aft... [more]

Background. To date, the earliest stage at which the orientation of the anterior-posterior axis in the mouse embryo is distinguishable by asymmetric gene expression is shortly after E5.5. At E5.5, prospective anterior markers are expressed at the distal tip of the embryo, whereas prospective posterior markers are expressed more proximally, close to the boundary with the extraembryonic region. Results. To contribute to elucidating the mechanisms underlying the events involved in early patterning of the mouse embryo, we have carried out a microarray screen to identify novel genes that are differentially expressed between the distal and proximal parts of the E5.5 embryo. Secondary screening of resulting candidates by in situ hybridisation at E5.5 and E6.5 revealed novel expression patterns for known and previously uncharacterised genes, including Peg10, Ctsz1, Cubilin, Jarid1b, Ndrg1, Sfmbt2, Gjb5, Talia and Plet1. The previously undescribed gene Talia and recently identified Plet1 are expressed specifically in the distal-most part of the extraembryonic ectoderm, adjacent to the epiblast, and are therefore potential candidates for regulating early patterning events. Talia and the previously described gene XE7 define a gene family highly conserved among metazoans and with a predicted protein structure suggestive of a post-transcriptional regulative function, whilst Plet1 appears to be mammal-specific and of unknown function. Conclusion. Our approach has allowed us to compare expression between dissected parts of the egg cylinder and has identified multiple genes with novel expr ession patterns at this developmental stage. These genes are potential candidates for regulating tissue interactions following implantation. © 2007 Frankenberg et al; licensee BioMed Central Ltd.

DOI 10.1186/1471-213X-7-8
Citations Scopus - 29
2006 Cox S, Smith L, Bogani D, Cheeseman M, Siggers P, Greenfield A, 'Sexually dimorphic expression of secreted frizzled-related (SFRP) genes in the developing mouse Müllerian duct.', Mol Reprod Dev, 73 1008-1016 (2006)
DOI 10.1002/mrd.20507
Citations Scopus - 13
2005 Price TS, Regan R, Mott R, Hedman A, Honey B, Daniels RJ, et al., 'SW-ARRAY: A dynamic programming solution for the identification of copy-number changes in genomic DNA using array comparative genome hybridization data', Nucleic Acids Research, 33 3455-3464 (2005)

Comparative genome hybridization (CGH) to DNA microarrays (array CGH) is a technique capable of detecting deletions and duplications in genomes at high resolution. However, array ... [more]

Comparative genome hybridization (CGH) to DNA microarrays (array CGH) is a technique capable of detecting deletions and duplications in genomes at high resolution. However, array CGH studies of the human genome noting false negative and false positive results using large insert clones as probes have raised important concerns regarding the suitability of this approach for clinical diagnostic applications. Here, we adapt the Smith-Waterman dynamic-programming algorithm to provide a sensitive and robust analytic approach (SW-ARRAY) for detecting copy-number changes in array CGH data. In a blind series of hybridizations to arrays consisting of the entire tiling path for the terminal 2 Mb of human chromosome 16p, the method identified all monosomies between 267 and 1567 kb with a high degree of statistical significance and accurately located the boundaries of deletions in the range 267-1052 kb. The approach is unique in offering both a nonparametric segmentation procedure and a nonparametric test of significance. It is scalable and well-suited to high resolution whole genome array CGH studies that use array probes derived from large insert clones as well as PCR products and oligonucleotides. © The Author 2005. Published by Oxford University Press. All rights reserved.

DOI 10.1093/nar/gki643
Citations Scopus - 71
2003 Smith L, 'DNA microarrays and development', Human Molecular Genetics, 12 1R-8 (2003)
DOI 10.1093/hmg/ddg053
2003 Smith L, Greenfield A, 'DNA microarrays and development', Human Molecular Genetics, 12 (2003)

Gene expression is a central concept in molecular biology: its control, frequently exquisite in terms of cell specificity and timing, forms part of our explanation of most biologi... [more]

Gene expression is a central concept in molecular biology: its control, frequently exquisite in terms of cell specificity and timing, forms part of our explanation of most biological processes. The importance of the control of gene expression for developmental biologists is made obvious by just considering the nature of their discipline. Development is the term we use to describe the coordination in time and space of numerous cellular activities such as mitosis, migration, differentiation and apoptosis. Understanding the role of genes in these processes thus necessitates the use of methods to determine patterns of transcription during development with a high degree of sensitivity and specificity, conventionally by in situ hybridization. However, there is a widespread conviction amongst biologists that the description of gene expression patterns is of no immediate functional relevance: definitive functional data are the exclusive prerogative of biochemistry and genetics. In this review of recent applications of DNA microarray technology by developmental biologists, we suggest that genome-wide expression profiling has met with some resistance owing to such preconceived ideas about the status of gene expression pattern descriptions and, in particular, the format in which these are delivered by microarrays.

Citations Scopus - 42
2003 Smith L, Van Hateren N, Willan J, Romero R, Blanco G, Siggers P, et al., 'Candidate testis-determining gene, maestro (Mro), encodes a novel HEAT repeat protein', Developmental Dynamics, 227 600-607 (2003)

Mammalian sex determination depends on the presence or absence of SRY transcripts in the embryonic gonad. Expression of SRY initiates a pathway of gene expression resulting in tes... [more]

Mammalian sex determination depends on the presence or absence of SRY transcripts in the embryonic gonad. Expression of SRY initiates a pathway of gene expression resulting in testis development. Here, we describe a novel gene potentially functioning in this pathway using a cDNA microarray screen for genes exhibiting sexually dimorphic expression during murine gonad development. Maestro (Mro) transcripts are first detected in the developing male gonad before overt testis differentiation. By 12.5 days postcoitus (dpc), Mro transcription is restricted to the developing testis cords and its expression is not germ cell-dependent. No expression is observed in female gonads between 10.5 and 14.5 dpc. Maestro encodes a protein containing HEAT-like repeats that localizes to the nucleolus in cell transfection assays. Maestro maps to a region of mouse chromosome 18 containing a genetic modifier of XX sex reversal. We discuss the possible function of Maestro in light of these data. © 2003 Wiley-Liss, Inc.

DOI 10.1002/dvdy.10342
Citations Scopus - 18
2003 Smith L, Underhill P, Pritchard C, Tymowska-Lalanne Z, Abdul-Hussein S, Hilton H, et al., 'Single primer amplification (SPA) of cDNA for microarray expression analysis', Nucleic acids research, 31 e9 (2003)

The potential of expression analysis using cDNA microarrays to address complex problems in a wide variety of biological contexts is now being realised. A limiting factor in such a... [more]

The potential of expression analysis using cDNA microarrays to address complex problems in a wide variety of biological contexts is now being realised. A limiting factor in such analyses is often the amount of RNA required, usually tens of micrograms. To address this problem researchers have turned to methods of improving detection sensitivity, either through increasing fluorescent signal output per mRNA molecule or increasing the amount of target available for labelling by use of an amplification procedure. We present a novel DNA-based method in which an oligonucleotide is incorporated into the 3' end of cDNA during second-strand cDNA synthesis. This sequence provides an annealing site for a single complementary heel primer that directs Taq DNA polymerase amplification of cDNA following multiple cycles of denaturation, annealing and extension. The utility of this technique for transcriptome-wide screening of relative expression levels was compared to two alternative methodologies for production of labelled cDNA target, namely incorporation of fluorescent nucleotides by reverse transcriptase or the Klenow fragment. Labelled targets from two distinct mouse tissues, adult liver and kidney, were compared by hybridisation to a set of cDNA microarrays containing 6500 mouse cDNA probes. Here we demonstrate, through a dilution series of cDNA derived from 10 micro g of total RNA, that it is possible to produce datasets comparable to those produced with unamplified targets with the equivalent of 30 ng of total RNA. The utility of this technique for microarray analysis in cases where sample is limited is discussed.

DOI 10.1093/nar/gng009
Citations Scopus - 51
2002 Siggers P, Smith L, Greenfield A, 'Sexually dimorphic expression of Gata-2 during mouse gonad development', Mechanisms of Development, 111 159-162 (2002)

We report that Gata-2 is expressed in a sexually dimorphic fashion during mouse gonadogenesis. Gata-2 transcripts accumulate rapidly in the fetal ovary from 11.5 days post coitum ... [more]

We report that Gata-2 is expressed in a sexually dimorphic fashion during mouse gonadogenesis. Gata-2 transcripts accumulate rapidly in the fetal ovary from 11.5 days post coitum (dpc) onwards, but are not detected in the fetal testis throughout the period studied (10.5-15.5 dpc). Ovarian expression of Gata-2 ceases by 15.5 dpc. Examination of ovaries from embryos homozygous for the extreme allele of c-kit(W e ) (Nature, 335, 88; Cell, 55, 185) demonstrates that ovarian Gata-2 expression is dependent upon the presence of germ cells. Comparative in situ hybridisation using the germ cell marker Oct4 (EMBO J., 8, 2543) indicates that Gata-2 transcripts are restricted to the germ cell lineage at 13.5 dpc. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

DOI 10.1016/S0925-4773(01)00602-5
Citations Scopus - 33
2001 Ryder CD, Smith LB, Teakle GR, King GJ, 'Contrasting genome organisation: two regions of the Brassica oleracea genome compared with collinear regions of the Arabidopsis thaliana genome.', Genome, 44 808-817 (2001)
2000 Grimmond S, Van Hateren N, Siggers P, Arkell R, Larder R, Soares MB, et al., 'Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggests a role in mammalian sexual development', Human Molecular Genetics, 9 1553-1560 (2000)

The mammalian sex-determining pathway is controlled by the presence or absence of SRY expression in the embryonic gonad. Expression of SRY in males is believed to initiate a pathw... [more]

The mammalian sex-determining pathway is controlled by the presence or absence of SRY expression in the embryonic gonad. Expression of SRY in males is believed to initiate a pathway of gene expression resulting in testis development. In the absence of SRY, ovary development ensues. Several genes have now been placed in this pathway but our understanding of it is far from complete and several functional classes of protein appear to be absent. Sex-determining genes frequently exhibit sexually dimorphic patterns of expression in the developing gonad both before and after overt differentiation of the testis or ovary. In order to identify additional sex-determining or gonadal differentiation genes we have examined gene expression in the developing gonads of the mouse using cDNA microarrays constructed from a normalized urogenital ridge library. We screened for genes exhibiting sexually dimorphic patterns of expression in the gonad at 12.5 and 13.5 days post-coitum, after overt gonad differentiation, by comparing complex cDNA probes derived from male and female gonadal tissue at these stages on microarrays. Using in situ hybridization analysis we show here that two genes identified by this screen, protease nexin-1 (Pn-1) and vanin-1 (Vnn1), exhibit male-specific expression prior to overt gonadal differentiation and are detected in the somatic portion of the developing gonad, suggesting a possible direct link to the testis-determining pathway for both genes.

Citations Scopus - 92
Show 67 more journal articles

Conference (3 outputs)

Year Citation Altmetrics Link
2016 Macdonald J, Smith LB, Anderson RA, Mitchell RT, 'Spatiotemporal profiling of luteinising hormone/human choriogonadotropin receptor in the human fetal testis', LANCET, Royal Coll Phys, London, ENGLAND (2016)
2010 McInnes KJ, Smith LB, Saunders PTK, Andrew R, Walker BR, 'Adipose-Specific Knockout of Androgen Receptors in Male Mice Results in Altered Adipose Gene Expression, Hyperinsulinemia and Hypertriglyceridemia without Obesity', ENDOCRINE REVIEWS, San Diego, CA (2010)
2010 Welsh M, Moffat L, McNeilly A, Saunders PTK, Sharpe RM, Smith LB, 'New Model for Age-Related Prostatic Disease: Smooth Muscle Cell-Specific Knockout of Androgen Receptor.', ENDOCRINE REVIEWS, San Diego, CA (2010)
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Grants and Funding

Summary

Number of grants 24
Total funding $23,451,831

Click on a grant title below to expand the full details for that specific grant.


20172 grants / $1,017,904

Translation of an androgen-miRNA sterilant$1,016,775

Funding body: Found Animals Foundation Inc

Funding body Found Animals Foundation Inc
Project Team

Prof LB Smith (PI)

Scheme Michelson Grants in Reproductive Biology
Role Lead
Funding Start 2017
Funding Finish 2020
GNo
Type Of Funding External
Category EXTE
UON N

Society for Reproduction and Fertility – International Collaboration$1,129

Funding body: Society for Reproduction and Fertility

Funding body Society for Reproduction and Fertility
Scheme Travel Award
Role Lead
Funding Start 2017
Funding Finish 2017
GNo
Type Of Funding External
Category EXTE
UON N

20163 grants / $4,756,835

Androgens: Unlocking the key drivers of men's health$3,749,564

Funding body: Medical Research Council (UK)

Funding body Medical Research Council (UK)
Project Team

Prof LB Smith (PI)

Scheme Programme Grant
Role Lead
Funding Start 2016
Funding Finish 2021
GNo
Type Of Funding External
Category EXTE
UON N

How does pituitary androgen signalling support lifelong health and wellbeing? An integrated transgenic and systems biology approach$920,072

Funding body: Biotechnology and Biological Sciences Research Council (BBSRC)

Funding body Biotechnology and Biological Sciences Research Council (BBSRC)
Project Team

Prof LB Smith (PI)

Scheme Research Grant
Role Lead
Funding Start 2016
Funding Finish 2019
GNo
Type Of Funding External
Category EXTE
UON N

Role of vascular androgen receptor in advanced atherosclerosis$87,199

Funding body: Wellcome Trust

Funding body Wellcome Trust
Scheme ISSF Project Grant
Role Investigator
Funding Start 2016
Funding Finish 2017
GNo
Type Of Funding External
Category EXTE
UON N

20152 grants / $145,317

PhD tissue repair studentship award (open competition)$141,415

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Prof LB Smith (PI)

Scheme Award
Role Lead
Funding Start 2015
Funding Finish 2018
GNo
Type Of Funding Internal
Category INTE
UON N

A new UK-wide Virtual Centre for men's health research$3,902

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Prof LB Smith (PI)

Scheme Innovation Initiative Grant
Role Lead
Funding Start 2015
Funding Finish 2016
GNo
Type Of Funding Internal
Category INTE
UON N

20142 grants / $5,299,017

Initial Training Network GROWSPERM: Development of in vitro and in vivo strategies to avoid and cure male infertility$5,187,339

Funding body: European Commission, European Union

Funding body European Commission, European Union
Project Team

Edinburgh PI, RT Mitchell, Edinburgh Co-I, LB Smith

Scheme 7th Research Framework Programme
Role Investigator
Funding Start 2014
Funding Finish 2018
GNo
Type Of Funding External
Category EXTE
UON N

PhD studentship award (open competition)$111,678

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Prof LB Smith (PI)

Scheme Award
Role Lead
Funding Start 2014
Funding Finish 2017
GNo
Type Of Funding External
Category EXTE
UON N

20135 grants / $866,176

Sterilization via disruption of androgen signaling in Sertoli and Granulosa cells: Proof of concept study in mice$633,049

Funding body: Found Animals Foundation Inc

Funding body Found Animals Foundation Inc
Project Team

Dr LB Smith (PI), Dr P Brown

Scheme Michelson Grants in Reproductive Biology
Role Lead
Funding Start 2013
Funding Finish 2016
GNo
Type Of Funding Internal
Category INTE
UON N

PhD Studentship Award: Establishing the cause-consequence relationship between age-related reduction in androgens and normal ageing processes $113,400

Funding body: EASTBio

Funding body EASTBio
Project Team

Prof LB Smith (PI)

Scheme BBSRC
Role Lead
Funding Start 2013
Funding Finish 2017
GNo
Type Of Funding External
Category EXTE
UON N

Charles Darwin PhD Scholarship with Gordon Lennie Bursary Award$70,115

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Tina Tsai (Student), Dr LB Smith (PI)

Scheme Award
Role Lead
Funding Start 2013
Funding Finish 2016
GNo
Type Of Funding Internal
Category INTE
UON N

Global PhD Scholarship Award$46,744

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Tina Tsai (Student), Dr LB Smith (PI)

Scheme Award
Role Lead
Funding Start 2013
Funding Finish 2016
GNo
Type Of Funding Internal
Category INTE
UON N

Characterization of a novel mouse model of induced androgen receptor expression $2,868

Funding body: Medical Research Scotland

Funding body Medical Research Scotland
Project Team

Prof LB Smith (PI)

Scheme Research Grant
Role Investigator
Funding Start 2013
Funding Finish 2013
GNo
Type Of Funding External
Category EXTE
UON N

20123 grants / $1,750,708

Integrating systems biology and transgenic technologies to unlock the secrets of Sertoli cell development and function$1,177,061

Funding body: Biotechnology and Biological Sciences Research Council (BBSRC)

Funding body Biotechnology and Biological Sciences Research Council (BBSRC)
Project Team

Dr LB Smith (PI), Prof P O’Shaughnessy, Prof T Freeman

Scheme Research Grant
Role Lead
Funding Start 2012
Funding Finish 2015
GNo
Type Of Funding External
Category EXTE
UON N

Cell-Specific Action of Androgen Receptor in Cardiovascular Function, Response and Repair$440,590

Funding body: British Heart Foundation

Funding body British Heart Foundation
Project Team

Dr LB Smith (PI), Dr PWF Hadoke, Dr M Denvir

Scheme Research Grant
Role Lead
Funding Start 2012
Funding Finish 2015
GNo
Type Of Funding External
Category EXTE
UON N

Control of Leydig cell function and regeneration$133,057

Funding body: MRC Medical Research Council UK

Funding body MRC Medical Research Council UK
Project Team

Dr LB Smith (PI), Prof Richard Sharpe

Scheme Research Grant
Role Lead
Funding Start 2012
Funding Finish 2015
GNo
Type Of Funding Internal
Category INTE
UON N

20112 grants / $8,998,615

Testis Development and Function in Relation to Disorders of Reproductive and General Health in Males$5,059,479

Funding body: MRC Medical Research Council UK

Funding body MRC Medical Research Council UK
Project Team

Prof RM Sharpe (PI), Dr LB Smith

Scheme Research Grant
Role Investigator
Funding Start 2011
Funding Finish 2016
GNo
Type Of Funding External
Category EXTE
UON N

Genetic and Hormonal Determinants of Male Reproductive Health and Fertility$3,939,136

Funding body: MRC Medical Research Council UK

Funding body MRC Medical Research Council UK
Project Team

Dr LB Smith (PI)

Scheme Research Grant
Role Lead
Funding Start 2011
Funding Finish 2016
GNo
Type Of Funding External
Category EXTE
UON N

20092 grants / $178,648

Cell-cell synergism in androgen control of testis function$172,447

Funding body: MRC Medical Research Council UK

Funding body MRC Medical Research Council UK
Project Team

Dr LB Smith (PI) Prof Philippa Saunders

Scheme PhD Studentship
Role Lead
Funding Start 2009
Funding Finish 2012
GNo
Type Of Funding External
Category EXTE
UON N

Identifying a novel gene that causes obesity. Investigators$6,200

Funding body: University of Edinburgh

Funding body University of Edinburgh
Project Team

Dr K McInnes (PI), Dr LB Smith

Scheme Research Grant
Role Investigator
Funding Start 2009
Funding Finish 2009
GNo
Type Of Funding Internal
Category INTE
UON N

20082 grants / $232,292

Genetic mapping of a novel, spontaneous, early-onset mouse model of Aortic Aneurysm with acute Dissection (AAD)$210,787

Funding body: British Heart Foundation

Funding body British Heart Foundation
Project Team

Dr LB Smith (PI), Dr PWF Hadoke, Dr M Denvir, Dr D Brownstein

Scheme Research Grant
Role Lead
Funding Start 2008
Funding Finish 2010
GNo
Type Of Funding External
Category EXTE
UON N

Androgens and sex-specific risk of cardiovascular disease$21,505

Funding body: Tenovus Scotland

Funding body Tenovus Scotland
Project Team

Dr LB Smith (PI), Dr PWF Hadoke, Dr M Denvir

Scheme Research Grant
Role Lead
Funding Start 2008
Funding Finish 2009
GNo
Type Of Funding External
Category EXTE
UON N

20071 grants / $206,319

Androgen signalling in a novel model of male infertility$206,319

Funding body: MRC Medical Research Council UK

Funding body MRC Medical Research Council UK
Project Team

Dr LB Smith (PI), Prof Philippa Saunders

Scheme PhD Studentship
Role Lead
Funding Start 2007
Funding Finish 2010
GNo
Type Of Funding Internal
Category INTE
UON N
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Research Supervision

Number of supervisions

Completed2
Current6

Current Supervision

Commenced Level of Study Research Title Program Supervisor Type
2017 Masters The role of Srd5a1 in testicular function Medical Science, University of Edinburgh Co-Supervisor
2017 PhD The impact of ageing on testicular endocrinology and function Medical Science, University of Edinburgh Co-Supervisor
2016 Masters Defining pituitary stem cell populations in the male mouse Medical Science, University of Edinburgh Co-Supervisor
2015 PhD Tissue repair in the testis through gene therapy Medical Science, University of Edinburgh Co-Supervisor
2014 PhD The role of androgen signalling in the adrenal gland Medical Science, University of Edinburgh Co-Supervisor
2013 PhD The impact of ageing on testicular endocrinology and function Medical Science, University of Edinburgh Co-Supervisor

Past Supervision

Year Level of Study Research Title Program Supervisor Type
2014 Masters The role of Sertoli cell population size in testis function Medical Science, University of Edinburgh Co-Supervisor
2014 Masters The role of androgen receptor in pituitary function Medical Science, University of Edinburgh Co-Supervisor
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Professor Lee Smith

Position

Pro Vice-Chancellor
Office of the PVC, Faculty of Science
Office PVC - Science
Faculty of Science

Contact Details

Email lee.smith@newcastle.edu.au
Phone (02) 4921 5906
Mobile 0437075039
Fax (02) 4921 7949

Office

Room V201A
Building Mathematics
Location Callaghan
University Drive
Callaghan, NSW 2308
Australia
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